Therapeutically active cyclopentanes

ABSTRACT

Disclosed herein are compounds having a formula: 
     
       
         
         
             
             
         
       
     
     Therapeutic methods, medicaments, and compositions related thereto are also disclosed.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/299,562, filed Jan. 29, 2010, the disclosure of which is herebyincorporated in its entirety herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to compounds and methods fortreating ocular disorders. The invention relates specifically to the useof certain well-defined cyclopentanes for the treatment of ocularhypertension and glaucoma.

BACKGROUND OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage. Considering all types together,glaucoma occurs in about 2% of all persons over the age of 40 and may beasymptotic for years before progressing to rapid loss of vision. Incases where surgery is not indicated, topical β-adrenoreceptorantagonists have traditionally been the drugs of choice for treatingglaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

SUMMARY OF THE INVENTION

The invention provides well-defined cyclopentanes for treating glaucomaand ocular hypertension. In one embodiment of the invention, there areprovided compounds having the structure:

wherein:

-   -   Y is —Cl, —F, —Br, —CN, or —CF₃;    -   X C₀-C₁₄ optionally substituted alkylene, optionally substituted        alkenylene, or optionally substituted alkynylene;    -   Z is optionally substituted methylene or C₂-C₁₄ optionally        substituted alkylene, optionally substituted alkenylene, or        optionally substituted alkynylene;    -   E is interarylene or interheteroarylene;    -   R is H, C₁₋₆ alkyl, phenyl, —CH₂CH₂OH, or —CH₂CH₂—N(R¹)₂ wherein        R¹ is C₁ to C₆ alkyl, or each R¹ taken together with the        nitrogen atom forms a ring optionally containing an additional        heteroatom; and    -   A is optionally substituted cycloalkyl or optionally substituted        cycloalkenyl;        or pharmaceutically acceptable salts, hydrates, solvates, and        crystal forms, isomers, tautomers, enantiomers, and        diastereomers thereof.

In another embodiment of the invention, there are provided compositionsincluding at least one compound of the invention, wherein thecomposition is a liquid which is ophthalmically acceptable.

In another embodiment of the invention there are provided methods fortreating glaucoma or ocular hypertension. Such methods can be performed,for example, by administering to a subject in need thereof a compound ofthe invention.

In still another embodiment of the invention, there are provided kitsincluding at least one composition of the invention, a container, andinstructions for administration of the composition to a subject in needthereof for the treatment of glaucoma or ocular hypertension.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise. As used herein, “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“includes,” and “included,” is not limiting. The section headings usedherein are for organizational purposes only and are not to be construedas limiting the subject matter described.

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques ofanalytical chemistry, synthetic organic and inorganic chemistrydescribed herein are those known in the art. Standard chemical symbolsare used interchangeably with the full names represented by suchsymbols. Thus, for example, the terms “hydrogen” and “H” are understoodto have identical meaning Standard techniques may be used for chemicalsyntheses, chemical analyses, and formulation.

As used herein, “alkyl” refers to straight or branched chain hydrocarbylgroups having from 1 up to about 100 carbon atoms. Whenever it appearsherein, a numerical range, such as “1 to 100” or “C₁-C₁₀₀”, refers toeach integer in the given range; e.g., “C₁-C₁₀₀ alkyl” means that analkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 100 carbon atoms, although the term“alkyl” also includes instances where no numerical range of carbon atomsis designated. “Substituted alkyl” refers to alkyl moieties bearingsubstituents including alkyl, alkenyl, alkynyl, hydroxy, oxo, alkoxy,mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substitutedheterocyclic, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, halogen, haloalkyl, cyano,nitro, nitrone, amino, lower alkylamino, lower alkyldiamino, amido,azido, —C(O)H, —C(O)R_(D), —CH₂OR₇, —C(O)—, —C(O)—, —S—, —S(O)₂,—OC(O)—O—, wherein R₇ is H or lower alkyl, acyl, oxyacyl, carboxyl,carbamate, sulfonyl, sulfonamide, sulfuryl, and the like. As usedherein, “lower alkyl” refers to alkyl moieties having from 1 to about 6carbon atoms.

As used herein, the term “alkylene” refers to a divalent alkyl moiety,meaning the alkylene moiety is attached to the rest of the molecule atboth ends of the alkyl unit.

As used herein, “alkenyl” refers to straight or branched chainhydrocarbyl groups having at least one carbon-carbon double bond, andhaving in the range of about 2 up to about 100 carbon atoms, and“substituted alkenyl” refers to alkenyl groups further bearing one ormore substituents as set forth above. As used herein, “lower alkenyl”refers to alkenyl moieties having from 2 to about 6 carbon atoms.

As used herein, the term “alkenylene” refers to a divalent alkenylmoiety, meaning the alkenylene moiety is attached to the rest of themolecule at two positions.

As used herein, “alkynyl” refers to straight or branched chainhydrocarbyl groups having at least one carbon-carbon triple bond, andhaving in the range of about 2 up to about 100 carbon atoms, and“substituted alkynyl” refers to alkynyl groups further bearing one ormore substituents as set forth above. As used herein, “lower alkynyl”refers to alkynyl moieties having from 2 to about 6 carbon atoms.

As used herein, “cycloalkyl” refers to cyclic (i.e., ring-containing)alkyl moieties typically containing in the range of about 3 up to about8 carbon atoms, and “substituted cycloalkyl” refers to cycloalkyl groupsfurther bearing one or more substituents as set forth above.“Cycloalkyl” also refers to bicyclic moieties, such as norbornyl, andthe like.

As used herein, “cycloalkenyl” refers to cyclic (i.e., ring-containing)alkenyl moieties typically containing in the range of about 3 up toabout 8 carbon atoms, and “substituted cycloalkenyl” refers tocycloalkenyl groups further bearing one or more substituents as setforth above. “Cycloalkenyl” also refers to bicyclic moieties, such asnorbornenyl, and the like.

As used herein, “aryl” refers to aromatic groups having in the range of5 up to 14 carbon atoms and “substituted aryl” refers to aryl groupsfurther bearing one or more substituents as set forth above.

As used herein, “heteroaryl” refers to aromatic moieties containing oneor more heteroatoms (e.g., N, O, S, or the like) as part of the ringstructure and having in the range of 5 up to 14 total atoms in the ringstructure (i.e., carbon atoms and heteroatoms). “Substitutedheterocyclic” refers to heterocyclic groups further bearing one or moresubstituents as set forth above.

As used herein “interarylene” refers to an aryl ring or ring system or aheteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or interheteroarylene may be substituted orunsubstituted. Unsubstituted interarylene or interheteroarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or interheteroarylene has substituents inaddition to the two parts of the molecule it connects.

As used herein, “heterocyclic” refers to non-aromatic cyclic (i.e.,ring-containing) groups containing one or more heteroatoms (e.g., N, O,S, or the like) as part of the ring structure, and having in the rangeof 3 up to 14 carbon atoms and “substituted heterocyclic” refers toheterocyclic groups further bearing one or more substituents as setforth above.

As used herein, “halogen” or “halide” refers to fluoride, chloride,bromide or iodide. “Fluoride, chloride, bromide or iodide” may also bereferred to as “fluoro, chloro, bromo, or iodo”.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The invention provides well-defined cyclopentanes having the structure:

wherein:

-   -   Y is —Cl, —F, —Br, —CN, or —CF₃;    -   X is C₀-C₁₄ optionally substituted alkylene, optionally        substituted alkenylene, or optionally substituted alkynylene;    -   Z is optionally substituted methylene or C₂-C₁₄ optionally        substituted alkylene, optionally substituted alkenylene, or        optionally substituted alkynylene;    -   E is interarylene or interheteroarylene;    -   R is H, C₁₋₆ alkyl, phenyl, —CH₂CH₂OH, or —CH₂CH₂—N(R₁)₂ wherein        R¹ is C₁ to C₆ alkyl, or each R¹ taken together with the        nitrogen atom forms a ring optionally containing an additional        heteroatom; and    -   A is optionally substituted cycloalkyl or optionally substituted        cycloalkenyl;        or pharmaceutically acceptable salts, hydrates, solvates, and        crystal forms, isomers, tautomers, enantiomers, and        diastereomers thereof.

In some embodiments of the invention, Y is —Cl, —F, —CN, or —CF₃. In oneembodiment, Y is —Cl. In another embodiment Y is —F. In anotherembodiment Y is —CN. In another embodiment Y is —Br. In anotherembodiment Y is —CF₃.

In some embodiments of the invention, X and Z are each independentlyC₂-C₆ alkylene, alkenylene, or alkynylene. In certain embodiments, X isC₂ alkylene, alkenylene, or alkynylene. In certain embodiments, Z is C₃alkylene, alkenylene, or alkynylene.

In some embodiments of the invention the interarylene orinterheteroarylene is substituted or unsubstituted interphenylene,interthiophenylene, interfurylene, interpyridinylene, interoxazolylene,or interthiazolene. In certain embodiments of the invention, theinterarylene is interthiophenylene. In other embodiments theinterheteroarylene is furylene and interthiazolene.

In other embodiments of the invention A is cycloalkyl. In certainembodiments A is cyclopentyl or cyclohexyl.

The compounds of the invention may contain a wide a variety ofsubstituents. When invention compounds bear substituents, thesubstituents are typically selected from alkyl, alkenyl, alkynyl,hydroxy, alkoxy, heterocyclic, aryl, heteroaryl, aryloxy, halogen,haloalkyl, cyano, nitro, amino, lower alkylamino, lower dialkylamino,amido, azido, acyl (—C(O)R₆), alkoxymethyl, mercapto (—S—R₆), sulfoxy(—S(O)—R₆), sulfonyl (—S(O)₂—R₆), sulfonamide (—S(O)₂N(R₆)₂), carbonate(—OC(O)—O—R₆), oxyacyl (—OC(O)—R₆), carboxyl (—C(O)OH), ester(—C(O)OR₆), carbamate (—OC(O)—N(R₆)₂), wherein R₆ is H or lower alkyl,lower alkenyl, lower alkynyl, aryl, heteroaryl, heterocycle, and thelike.

In certain embodiments of the invention, Z, X, and A bear hydroxysubstituents.

Exemplary compounds contemplated for use in the practice of theinvention include, but are not limited to,

-   5-(3-((1R,2R,3R,5R)-5-chloro-3-hydroxy-2-(2-(1    pentylcyclohexyl)ethyl)cyclopentyl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((1R,2R,3R,5R)-5-chloro-3-hydroxy-2-(2-(1-pentylcyclohexyl)ethyl)cyclopentyl)propyl)thiophene-2-carboxylate;-   5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclopentylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclopentylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclopentylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;-   5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclopentylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic    acid;-   5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclohexylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic    acid;-   methyl    5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclohexylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;-   methyl    5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclohexylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;    or-   5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclohexylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic    acid.

In other embodiments of the invention, esters of invention compounds arecontemplated for use. As such, R consists of: 1) C₁₋₆ alkyl or phenyl,and 2) from 0 to 2 —OH moieties. In other words, examples of R include:

-   —CH₃, —C₂H₅, —C₃H₇, —C₄H₉, C₅H₁₁, —C₆H₁₃, cyclic —C₃H₆, cyclic    —C₄H₈, cyclic —C₅H₁₀, or cyclic —C₆H₁₂, wherein “cyclic” indicates    the presence of a ring;-   —CH₂—OH, —C₂H₄—OH, —C₃H₆—OH, —C₄H₈—OH, C₅H₁₀—OH, —C₆H₁₂—OH, cyclic    —C₃H₅OH, cyclic —C₄H₇—OH, cyclic —C₅H₉—OH, or cyclic —C₆H₁₁—OH,    wherein the —OH may be in any position on the hydrocarbyl moiety;-   —C₂H₃—(OH)₂, —C₃H₅—(OH)₂, —C₄H₇—(OH)₂, —C₅H₉—(OH)₂, or —C₆H₁₁—(OH)₂,    cyclic —C₃H₄—(OH)₂, cyclic —C₄H₆—(OH)₂, cyclic —C₅H₈—(OH)₂, or    cyclic —C₆H₁₀—(OH)₂, wherein —(OH)₂ represents 2 distinct —OH    moieties, and each —OH may be in any position on the hydrocarbyl    moiety; or

In other embodiments, ethyldialkylamino esters are contemplated for usein the practice of the invention. In this embodiment —CH₂CH₂—N(R¹)₂wherein R¹ is C₁ to C₆ alkyl, or each R¹ taken together with thenitrogen atom forms a ring optionally containing an additionalheteroatom.

Exemplary esters include, but are not limited to, the followingcompounds:

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring. Salts canform from or incorporate one or more deprotonated acidic groups (e.g.carboxylic acids), one or more protonated basic groups (e.g. amines), orboth (e.g. zwitterions).

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted.

Prodrug preparation is well known in the art. For example, “Prodrugs andDrug Delivery Systems,” which is a chapter in Richard B. Silverman,Organic Chemistry of Drug Design and Drug Action, 2d Ed., ElsevierAcademic Press: Amsterdam, 2004, pp. 496-557, provides further detail onthe subject. In particular, alkyl esters having such as methyl, ethyl,isopropyl, and the like are contemplated. Also contemplated are prodrugscontaining a polar group such as hydroxyl or morpholine. Examples ofsuch prodrugs include compounds containing the moieties —CO₂(CH₂)₂OH,

and the like.

The compounds of the invention are useful for reducing intraocularpressure. Reduction of intraocular pressure has been shown to delay orprevent the onset of primary open angle glaucoma, and to delay orprevent further vision loss in patients with primary open angleglaucoma. Thus, these compounds are also useful for treating glaucoma.Different types of suitable dosage forms and medicaments are well knownin the art, and can be readily adapted for delivery of the compoundsdisclosed herein. For example, the compound could be dissolved orsuspended in an aqueous solution or emulsion that is buffered to anappropriate pH, and administered topically to an eye of a mammal (seeU.S. Pat. No. 7,091,231).

For the purposes of this disclosure, “treat,” “treating,” or “treatment”refer to the use of a compound, composition, therapeutically activeagent, or drug in the diagnosis, cure, mitigation, treatment, orprevention of disease or other undesirable condition.

Unless otherwise indicated, reference to a compound should be construedbroadly to include pharmaceutically acceptable salts, prodrugs,tautomers, alternate solid forms, non-covalent complexes, andcombinations thereof, of a chemical entity of a depicted structure orchemical name.

Tautomers are isomers that are in rapid equilibrium with one another.For example, tautomers may be related by transfer of a proton, hydrogenatom, or hydride ion. Unless stereochemistry is explicitly andunambiguously depicted, a structure is intended to include everypossible stereoisomer, both pure or in any possible mixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be polymorphs, different kinds of amorphoussolid forms, glasses, and the like.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distcaratemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds ispreferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The following examples are intended only to illustrate the invention andshould in no way be construed as limiting the invention.

EXAMPLES Synthetic Methods

While there are many ways to prepare the compounds disclosed herein,useful compounds may be obtained by using or adapting the followingexemplary procedures.

-   -   Conditions: (a) LDA; n-pentyliodide, HMPA; (b) LiAlH₄; (c) Swern        [O]; (d) Ph₃PCH₃Br, tert-BuOK; (e) 9-BBN; H₂O₂; NaOH, H₂O; (f)        Ph₃P, I₂, imidazole, CH₂Cl₂.

Representative procedure: (E)-(2-iodovinyl)cyclopentane (1-2, n=1).Cp₂ZrHCl (1.805 g, 7.00 mmol) was added to a solution of alkyne 1-1(n=1,497 mg, 4.60 mmol) in CH₂Cl₂ (19 mL). The reaction was stirred for45 min. and N-iodosuccinimide (NIS, 1.552 g, 6.90 mmol) was added. After2 h, saturated NaHCO₃ solution (20 mL) was added and the resultingmixture was extracted with CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂solution was washed with brine and then was dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash chromatography using aCombiflash system by Teledyne Isco (40 g silica gel, 0→100% ethylacetate/hexanes) which gave the title compound (978 mg, 90%). Theintermediate iodides were converted to the final compounds (1-3) by asequence similar to that described in U.S. patent application Ser. No.12/265,062.

Methyl 1-pentylcyclohexanecarboxylate (2-2). A solution of ester 2-1(2.053 g, 14.4 mmol) in THF (22 mL) was added, by cannula, to a −78° C.solution of LDA (8 mL, 16 mmol, 2 M in heptanes/THF/ethyl benzene fromAldrich), rinsing with 1 mL THF. After 30 min., a solution ofn-pentyliodide (3.147 g, 15.9 mmol) in HMPA (2.6 mL) was added. Theresulting solution was stirred for 10 min. at −78° C. and then wasallowed to warm to room temperature. After 1 h, 100 mL H₂O was added.The resulting mixture was extracted with ethyl acetate and the ethylacetate solution was washed with H₂O (3×100 mL) and brine and then wasdried (Na₂SO₄), filtered and evaporated. The residue was purified byflash chromatography using a Combiflash system by Teledyne Isco (120 gsilica gel, 0→25% ethyl acetate/hexanes) which gave the title compound(1.773 g, 12.5 mmol, 87%).

(1-Pentylcyclohexyl)methanol (2-3). LiAlH₄ (15 mL, 30 mmol, 2 M/THF) wasadded drop wise to a solution of 2-2 (1.773 g, 12.5 mmol) in ether (9mL) at a rate to maintain a gentle reflux. The mixture was stirredfurther for 15 min. and then was cooled to 0° C. H₂O (1 mL) was addedfollowed by 3 M NaOH (1.2 mL) and more H₂O (3 mL). The resulting mixturewas allowed to warm to room temperature and after 1 h of stirring, 50 mLsaturated NH₄Cl solution was added. The mixture was extracted withdichloromethane (3×30 mL) and the combined dichloromethane solution waswashed with brine and then was dried (Na₂SO₄), filtered and evaporated.The residue was purified by flash chromatography using a combiflashsystem by Teledyne Isco (80 g silica gel, 0→100% ethyl acetate/hexanes)which gave the title compound (968 mg, 5.3 mmol, 42%).

1-Pentylcyclohexanecarbaldehyde (2-4). DMSO (930 L) was added to a −78°C. solution of oxalyl chloride (3.2 mL, 2 M/toluene) in CH₂Cl₂ (44 mL).After 15 min., a solution of alcohol 2-3 (968 mg, 5.3 mmol) in 14 mLCH₂Cl₂ was added by cannula, rinsing with 2 mL CH₂Cl₂. The reaction wasstirred for 15 min. and Et₃N (5.9 mL) was added. The reaction wasallowed to warm to 0° C. and after 2 h, 100 mL saturated NaHCO₃ solutionwas added. The resulting mixture was extracted with CH₂Cl₂ (3×) and thecombined CH₂Cl₂ solution was washed with H₂O and brine and then wasdried (Na₂SO₄), filtered and evaporated to give the title compound.

1-Pentyl-1-vinylcyclohexane (2-5). Tert-BuOK (2.2 mL, 2.2 mmol, 1 M/THF)was added to a solution of Ph₃PCH₃Br (1.42 mmol) in THF (7.2 mL). After1 h, a solution of aldehyde 2-4 (130 mg, 0.71 mmol) in THF (2 mL) wasadded by cannula, rinsing with 1 mL THF. The reaction was stirred atroom temperature for 2 h and was then quenched by addition of 10 mLsaturated NH₄Cl solution. The resulting mixture was extracted with ethylacetate (3×20 mL) and the combined ethyl acetate solution was dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashchromatography using a Combiflash system by Teledyne Isco (4 g silicagel, 0→50% ethyl acetate/hexanes) which gave the title compound (62 mg,0.34 mmol, 48%).

2-(1-Pentylcyclohexyl)ethanol (2-6). A solution of 2-5 (90 mg, 0.50mmol) in THF (3.4 mL) was added to a solution of 9-BBN dimer (206 mg,0.84 mmol) in THF (3 mL). The reaction was placed in a 60° C. oil bathand after 2.5 h, a solution of H₂O₂ (35%, 1.4 mL)/NaOH (0.5 M, 1.4mL)/H₂O (0.35 mL) was added. The reaction was heated to reflux for 1 hand then allowed to cool to room temperature. H₂O (20 mL) was added andthe mixture was extracted with ethyl acetate (3×25 mL). The combinedethyl acetate solution was washed with brine and then was dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashchromatography using a Combiflash system by Teledyne Isco (4 g silicagel, 0→30% ethyl acetate/hexanes) which gave the title compound (70 mg,71%).

1-(2-iodoethyl)-1-pentylcyclohexane (2-7). The procedure used to preparethe title compound was described in U.S. Pat. No. 7,091,231 B2.

5-(3-((1R,2R,3R,5R)-5-chloro-3-hydroxy-2-(2-(1-pentylcyclohexyl)ethyl)cyclopentyl)propyl)thiophene-2-carboxylicacid (2-8). The title compound was prepared using a sequence describedin U.S. patent application Ser. No. 12/265,062.

In Vivo Example

U.S. Pat. No. 7,091,231, incorporated by reference herein, describes themethods used to obtain the in vivo test results presented in Table 1.

TABLE 1 DOG MONKEY Conc. Max. Max. (g/100 IOP Max. IOP ENTRY STRUCTUREmL) (%) hyperemia (%) 1

0.005% 40 2.0 47

In Vitro Examples

U.S. Pat. No. 7,427,685 incorporated by reference herein, describes themethods used to obtain the in vitro data in Table 2 below.

EP2 OTHER cAMP Ca2+ EP4 RECEPTORS EC50 Ki EC50 Ca2+ Ki Ca2+ EntrySTRUCTURE (nM) (nM) (nM) EC50 (nM) (nM) EC50 (nM) 1

0.6 9 4 3070 2617 DP(259) NA: EP1, EP3, FP, IP, TP 2

0.9 10  3 1349 2737 DP(191), NA: EP1, EP3, FDP, IP, TP 3

0.2  0.8 12  6639 2154 DP(548), EP3(9052) NA: EP1, FP, IP, TP 4

0.5 4 7 3,322 2709 DP(2162), EP3(5221) NA: EP1, FP, IP, TP 5

152 1038   2412   9330 5059 NA: DP, EP1, EP3, FP, IP,

While this invention has been described with respect to these specificexamples, it is understood that other modifications and variations arepossible without departing from the spirit of the invention.

1. A compound having a formula:

wherein: Y is —Cl, —F, —Br, —CN, or —CF₃; X is C₀-C₁₄ optionallysubstituted alkylene, optionally substituted alkenylene, or optionallysubstituted alkynylene; Z is optionally substituted methylene or C₂-C₁₄optionally substituted alkylene, optionally substituted alkenylene, oroptionally substituted alkynylene; E is interarylene orinterheteroarylene; R is H, C₁₋₆ alkyl, phenyl, —CH₂CH₂OH, or—CH₂CH₂—N(R¹)₂ wherein R¹ is C₁ to C₆ alkyl, or each R¹ taken togetherwith the nitrogen atom forms a ring optionally containing an additionalheteroatom; and A is optionally substituted cycloalkyl or optionallysubstituted cycloalkenyl; or pharmaceutically acceptable salts,hydrates, solvates, and crystal forms, isomers, tautomers, enantiomers,and diastereomers thereof.
 2. The compound of claim 1 wherein X is C₂-C₆alkylene, alkenylene, or alkynylene.
 3. The compound of claim 1 whereinX is C₃ alkylene, alkenylene, or alkynylene.
 4. The compound of claim 1wherein Z is C₂-C₆ alkylene, alkenylene, or alkynylene.
 5. The compoundof claim 1 wherein X is C₂ alkylene, alkenylene, or alkynylene.
 6. Thecompound of claim 1 wherein A is cycloalkyl.
 7. The compound of claim 6wherein A is cyclopentyl or cyclohexyl.
 8. The compound of claim 1wherein the interarylene or interheteroarylene is substituted orunsubstituted interphenylene, interthiophenylene, interfurylene,interpyridinylene, interoxazolylene, or interthiazolene.
 9. The compoundof claim 8 wherein the interarylene is interthiophenylene.
 10. Thecompound of claim 1 selected from:5-(3-((1R,2R,3R,5R)-5-chloro-3-hydroxy-2-(2-(1pentylcyclohexyl)ethyl)cyclopentyl)propyl)thiophene-2-carboxylic acid;methyl5-(3-((1R,2R,3R,5R)-5-chloro-3-hydroxy-2-(2-(1-pentylcyclohexyl)ethyl)cyclopentyl)propyl)thiophene-2-carboxylate;5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclopentylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclopentylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;methyl5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclopentylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclopentylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylicacid;5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclohexylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylicacid; methyl5-(3-((1R,2R,3R,5R)-5-chloro-2-(2-cyclohexylethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;methyl5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclohexylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate;or5-(3-((1R,2R,3R,5R)-5-chloro-2-(E)-2-cyclohexylvinyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylicacid.
 11. The compound of claim 1 having the structure:


12. The compound of claim 1 having the structure:


13. The compound of claim 1 having the structure:


14. The compound of claim 1 having the structure:


15. A compound having the structure


16. A composition comprising at least one compound according to claim 1,wherein the composition is a liquid which is ophthalmically acceptable.17. A method of treating glaucoma or ocular hypertension comprisingadministering to a subject in need thereof a compound according toclaim
 1. 18. The method of claim 17 wherein the subject is human.
 19. Akit comprising the composition of claim 16, a container, andinstructions for administration of the composition to a subject in needthereof for the treatment of glaucoma or ocular hypertension.